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Therapeutic Plasma Exchange, Rituximab and IV Ig for Severe Acute Exacerbation of IPF Admitted in ICU (EXCHANGE-IPF)

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ClinicalTrials.gov Identifier: NCT03584802
Recruitment Status : Recruiting
First Posted : July 12, 2018
Last Update Posted : July 29, 2019
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Brief Summary:
Idiopathic pulmonary fibrosis (IPF) is a fibroproliferative, irreversible disease of unknown cause, occurring mainly in patients older than 50. IPF is a rare but fatal lung disease, with an estimated prevalence of 14 to 28/100000 and a median survival time of 3 years. Acute exacerbation of IPF (AE-IPF) is a major event of IPF, as it is responsible for the death of 30-50 % of IPF patients; its annual incidence varies between 5 and 10%. The current literature indicates that IPF is associated with the development of an auto-immunity process targeting epithelial and endothelial lung cells. Autoantibodies have been associated with a poorer prognosis. A study by DONAHOE et al. (Plos One, 2015) indicates that the combination of corticosteroids, plasma exchanges, rituximab and immunoglobulins may improve the prognosis of the most severe forms of AE-IPF. In that study, the observed survival rate in patients receiving this combination of treatment was 70% as compared with 20% in historical controls. This therapeutic combination approach is designed both to eliminate and inhibit the production of circulating antibodies targeting the lungs. Considering the high mortality rate of an AE-IPF episode and the potential benefit of such an original approach, a well-conducted randomized controlled trial is critical.

Condition or disease Intervention/treatment Phase
Exacerbation of Idiopathic Pulmonary Fibrosis Other: Therapeutic plasma exchanges Other: Conventional treatment of AE-IPF Not Applicable

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Therapeutic Plasma Exchange, Rituximab and Intravenous Immunoglobulins for Severe Acute Exacerbation of Idiopathic Pulmonary Fibrosis Admitted in ICU: an Open, Randomized, Controlled Trial
Actual Study Start Date : May 16, 2019
Estimated Primary Completion Date : October 1, 2020
Estimated Study Completion Date : March 1, 2021


Arm Intervention/treatment
Experimental: Experimental treatment of AE-IPF
The experimental group will receive a combination of: 1- Methylprednisolone bolus of 1g IV day 1, then 20 mg/day (or oral prednisolone equivalent) for 21 days; 2- Nine therapeutic plasma exchanges of 1,5x the estimated plasma volumes using albumin: saline (3:1) or fresh frozen plasma in case of an INR superior to 1,5, on days 1,2,3,5,7,9,11,13,15; followed by administration of low dose of intravenous immunoglobulin (100mg/kg) 3, Rituximab 1g IV on days 7 and 15 (after therapeutic plasma exchange and premedication) 4, Intravenous immunoglobulin 0,5g/kg/d on days 16 to 19,
Other: Therapeutic plasma exchanges
The patient will initially receive Methylprednisolone bolus of 1g i.v. day 1, then 20 mg/day (or oral prednisone equivalent) for 21 days; and then he will have nine therapeutic plasma exchanges of 1.5x the estimated plasma volumes using albumin:saline (3:1) or fresh frozen plasma in case of an INR superior to 1.5, on days 1,2,3,5,7,9,11,13,15; followed by administration of low dose of intravenous immunoglobulin (100 mg/kg). On days 7 and 15, the patient will receive rituximab 1 g i.v. on days 7 and 15 (after therapeutic plasma exchange and premedication); and intravenous immunoglobulin 0.5 g/kg/d on days 16 to 19.

Active Comparator: Conventional treatment of AE-IPF
Intravenous methylprednisolone bolus of 10mg/kg on day1, 2 and 3, then 1mg/kg/d for 1 week, and 0,75 mg/kg/d for 1 week, then 0,5 mg/kg/d for 1 week, and 0,25 mg/kg/d for 1 week, and 0,125 mg/kg/d until day 90. Shift to oral prednisone as soon as the oral route is available.
Other: Conventional treatment of AE-IPF
Conventional treatment of AE-IPF




Primary Outcome Measures :
  1. Overall mortality at day 28 after initiation of therapy (Day1) [ Time Frame: 28 days ]
    Overall mortality at day 28 after initiation of therapy (Day1)


Secondary Outcome Measures :
  1. Overall mortality at 12 months [ Time Frame: 12 months ]
    Overall mortality at 12 months

  2. Number of days alive without mechanical ventilation between day 1 and day 28 [ Time Frame: 28 days ]
    Number of days alive without mechanical ventilation

  3. Length of ICU- stay and hospital-stay [ Time Frame: 12 months ]
    Length of ICU- stay and hospital-stay

  4. Evolution of the SOFA score between day 1 and day 28 or discharge-day from ICU as appropriate (in case of death before Day 28, the last SOFA score collected will be 24 points) [ Time Frame: 28 days ]

    The Sequential Organ Failure Assessment (SOFA) score is calculated with the combination of 6 scores:

    • respiratory score with the parameter PaO2/ FiO2
    • neurological score with Mean arterial pressure parameter
    • hepatic score with bilirubin parameter
    • coagulation score with measure of platelets
    • renal score with creatinine parameter

    The total score will range to 0 at 24; 0 being the better outcome and 24 the worse.


  5. Variation of global extent of HRCT infiltrates between initial HRCT and Day 90 according to AKIRA et al [ Time Frame: 90 days ]
    Variation of global extent of HRCT infiltrates

  6. Changes in lung injury biomarkers in plasma (KL-6, SP-D) between day 1 and day 90 [ Time Frame: 90 days ]
    Changes in lung injury biomarkers in plasma

  7. Changes in circulating autoantibodies levels (anti-periplakin, anti-HSP70 and anti-vimentin antibodies) between day 1 and day 90 [ Time Frame: 90 days ]
    Changes in circulating autoantibodies levels

  8. Changes in the proportion of blood fibrocytes between day 1 and day 90 [ Time Frame: 90 days ]
    Changes in the proportion of blood fibrocytes between day 1 and day 90

  9. Proportion of patients with at least one episode of any healthcare-associated infection between inclusion and day 28 [ Time Frame: 28 days ]
    Proportion of patients with at least one episode of any healthcare-associated infection

  10. Proportion of catheter-linked complications between inclusion and day 16 [ Time Frame: 16 days ]
    Proportion of catheter-linked complications between inclusion and day 16

  11. Number of blood units transfused between inclusion and day 28 [ Time Frame: 28 days ]
    Number of blood units transfused between inclusion and day 28

  12. Proportion of major bleeding according to the International Society On Thrombosis and Haemostasis [ Time Frame: 28 days ]
    Proportion of major bleeding

  13. Proportion of patients with occurrence of an acute renal failure at day 28, according to the KDIGO guidelines [ Time Frame: 28 days ]
    Proportion of patients with occurrence of an acute renal failure

  14. Proportion of patients with anaphylactic reaction at day 28 [ Time Frame: 28 days ]
    Proportion of patients with anaphylactic reaction



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • ≥ 18 years of age and < 75 years
  • Admitted to ICU in the last 72 h
  • Definite or probable IPF diagnosis defined on 2011 ATS/ERS/JRS/ALAT guidelines or a possible usual interstitial pneumonia pattern on HRCT without etiology.
  • Definite AE-IPF according to the 2016 revised criteria:

    1. Previous or concurrent diagnosis of idiopathic pulmonary fibrosis (if the diagnosis of IPF is not previously established, this criterion can be met by the presence of radiologic and or histopathologic changes consistent with usual interstitial pneumonia (UIP) pattern on the current evaluation);
    2. Acute worsening or development of dyspnea typically of less than one-month duration;
    3. Computed tomography with new bilateral ground-glass opacity and/or consolidation superimposed on a background pattern consistent with a UIP pattern (if no previous computed tomography is available, the qualifier "new" can be dropped);
    4. Deterioration not fully explained by cardiac failure or fluid overload.
  • PaO2/FiO2 ratio < 200
  • Affiliation to the French social security
  • Written informed consent from the patient or a legal representative if appropriate

Exclusion Criteria:

  • Known hypersensitivity intravenous immunoglobulin or rituximab
  • Severe heart failure
  • Active and uncontrolled bacterial and, fungal or parasitic infection
  • Positive multiplex Polymerase Chain Reaction (PCR) for Influenzae A and B, and for Respiratory Syncytial Virus (VRS)
  • Deep Veinous Thrombosis or embolism pulmonary in the last six months
  • Prior exposures to human-murine chimeric antibodies
  • Ongoing treatment with a cellular immunosuppressant (e.g., cyclophosphamide, methotrexate, mycophenolate, azathioprine, calcineurin inhibitors, etc.)
  • Subject treated with more than 2 boluses of methylprednisolone in the last 72 hours
  • Subject treated with a cumulative dose higher than 500 mg of methylprednisolone in the last 48 hours
  • Uncorrectable coagulopathies or thrombocytopenia <30000/mm3
  • Active cancer (other than basal cell carcinoma of the skin)
  • Other source of immunosuppression (i.e. HIV infection, solid organ transplant, lymphoma or leukemia)
  • Pregnancy
  • Patient listed for lung transplantation
  • Patient on ExtraCorporeal Membrane Oxygenation (ECMO)
  • Patient with a do-not-intubate order at admission to ICU
  • Concurrent participation in other experimental trials

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03584802


Contacts
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Contact: Bruno CRESTANI, Professor 00 33 (1) 40 25 86 86 or 00 33 bruno.crestani@aphp.fr
Contact: Mathilde NEUVILLE, Doctor 00 33 (1) 40 25 77 98 mathilde.neuville@aphp.fr

Locations
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France
Hôpital Bichat Claude Bernard Recruiting
Paris, France, 75018
Contact: Bruno BC CRESTANI, Professor       bruno.crestani@aphp.fr   
Contact: Mathilde MN NEUVILLE, Doctor       m.neuville@hopital-foch.com   
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Investigators
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Principal Investigator: Bruno CRESTANI, Professor Assistance Publique - Hôpitaux de Paris

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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT03584802     History of Changes
Other Study ID Numbers: P160915J
First Posted: July 12, 2018    Key Record Dates
Last Update Posted: July 29, 2019
Last Verified: July 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Assistance Publique - Hôpitaux de Paris:
severe acute exacerbation of idiopathic pulmonary fibrosis

Additional relevant MeSH terms:
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Fibrosis
Pulmonary Fibrosis
Idiopathic Pulmonary Fibrosis
Idiopathic Interstitial Pneumonias
Pathologic Processes
Lung Diseases
Respiratory Tract Diseases
Lung Diseases, Interstitial
Rituximab
Immunoglobulins
Antibodies
Immunoglobulins, Intravenous
gamma-Globulins
Rho(D) Immune Globulin
Methylprednisolone Hemisuccinate
Prednisolone
Methylprednisolone
Methylprednisolone Acetate
Prednisolone acetate
Prednisolone hemisuccinate
Prednisolone phosphate
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents